Alzheimer's disease is a degenerative disorder of the central nervous system that results in a progressive loss of memory and other intellectual functions, such as reasoning, orientation, and judgement (Katzman, R., "Biological Aspects of Alzheimer's Disease," Banbury Report 15, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., (1983)). Alzheimer's disease occurs in sporadic and familial forms and, in the United States, affects about 600 people for every 100,000.
The earliest stages of Alzheimer's disease are characterized by "pre-amyloid" deposits of Alzheimer's .beta.-peptide (A.beta.), which are amorphous deposits of A.beta. found in many regions of the brain. A.beta. is a 39-42 amino acid peptide that is derived from an about 700 amino acid cellular protein of unknown function (Glenner, G. G and Wong, C. G., Biochem. Biophys. Res. Commun., 120:885-890 (1984)). As the disease progresses, neuritic plaques form in the higher centers of the brain, particularly the hippocampus, frontal cortex and amygdala, and also accumulate in the walls of cerebral and meningeal blood vessels more generally. These neuritic plaques consist of mature amyloid deposits which, when viewed in the electron microscope, appear as large numbers of 6-10 nm diameter filaments consisting of A.beta.. Amyloid deposits exhibit certain characteristic staining properties (Abraham, C. R. et al., Cell, 52:487-501 (1988)).
In addition to A.beta., mature Alzheimer amyloid deposits contain other proteins, in particular the protease inhibitor .alpha..sub.1 -antichymotrypsin (.alpha..sub.1 -ACT) (Abraham, C. R. et al., Cell, 52:487-501 (1988) and the lipid carrier protein Apolipoprotein E (ApoE) (Namba, Y. et al. Brain Research, 541:163 (1991) and Frangione, B., Neurosci. Lett. 135:235 (1992)). Surrounding the mature amyloid deposits is a halo of degenerating neurites.
A.beta. is apparently derived from a larger membrane-spanning precursor protein whose RNA is alternately spliced to yield several protein products (Seikoe, D. J., Science, 248:1058-1060). These observations suggested that the amyloid deposits in Alzheimer's disease could result from abnormal expression or posttranslational modification or processing of a normal molecule. Also intriguing was the finding that the gene encoding the amyloid protein precursor is located on chromosome 21, suggesting a common cause for the deposits observed in Down syndrome, caused by trisomy of chromosome 21, and Alzheimer's disease.
As mentioned above, some cases of Alzheimer's disease appear to be familial, and are inherited in an autosomal dominant fashion. Linkage analysis in four families pointed to a lesion on the long arm of chromosome 21 (St. GeorgeHyslop, P. H. et al., Science, 238:664-660 (1987)), which correlated well with the mapping data and similarities between Down syndrome and Alzheimer disease. Recently, hereditary cerebral hemorrhage with amyloidosis of Dutch origin was reported to be linked to the APP gene, and a point mutation in the coding region of the gene was identified (Van Broeckhoven, C. et al., Science, 248:1120-1122 (1990); Levy, E. et al., Science, 248:1124-1126 (1990)). Patients with this disease have a form of the .beta.-protein in amyloid deposits in meningeal and cerebral blood vessels.
However, other studies reported linkage of familial Alzheimer's disease to a locus on chromosome 21 distinct from the amyloid precursor protein (APP) gene (Tanzi, R. E. et al., Nature, 329:156-157 (1987); Van Broeckhoven, C. et al., Nature, 329:153-155 (1987)). Furthermore, there was no evidence of duplication of the APP gene in cases of familial or sporadic disease. In fact, studies of some families reportedly indicate no linkage to chromosome 21 (Schellenberg, G. D., Science, 241:1507-1510 (1988)). These data suggest that there may be genetic heterogeneity in the cause of inherited forms of Alzheimer's disease, and other locations for the disease gene have been proposed, such as chromosome 14 (Weitkamp, L. R., Amer. J. Hum. Genet., 35:443-453 (1983) and Schellenberg, G. D. et al. Science, 258:668 (1992)).
Thus, other components of neuritic plaques that are associated with the mature amyloid deposits may also be of interest and may provide clues to the cause or progress of the disease. These components may also be involved in the neuropathology of the disease and consequently may provide targets for therapeutic drugs which slow the progress or alleviate the symptoms of the disease.